Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by bilateral acoustic schwannomas. In humans, these tumors result from mutations in the NF2 gene while in rodents, schwannomas have transforming mutations in the neu proto-oncogene. Rat schwannoma cell lines and human schwannomas have elevated expression of members of the CD44 family of glycoproteins (compared to normal Schwann cells). Some of these proteins inhibit neurite outgrowth in vitro, suggesting that they have a role in nerve development. Over-expression of the NF2 gene product, merlin, in rat schwannoma cells results in decreased CD44 expression and inhibition of tumorigenicity. These data suggest that merlin regulates CD44 expression and plays a regulatory role in Neu signalling, and that CD44 contributes to Schwann cell tumorigenesis. Two goals of this research project, therefore, are to determine the role of CD44 in normal peripheral nerve development and in Schwann cell tumor formation. The expression of CD44 proteins and their ability to influence neurite outgrowth at different stages of trigeminal nerve development will be examined. The effects of over-expressing or blocking CD44 on schwannoma growth will also be determined. A final goal is to determine how merlin influences Neu-induced signal transduction and CD44 expression by examining signalling pathways common to all three proteins. These studies should provide a better understanding of merlin's role in signal transduction and demonstrate whether CD44 is linked to NF2 pathogenesis.